Process for preparing 3-aryl-benzo{b} thiophenes

ABSTRACT

The present invention relates to a process for preparing a compound of formula (I): which includes cyclodehydrating a compound of formula (II): in the presence of an acid activated clay or acid activated zeolite catalyst and in the presence of a suitable solvent

This application is 35 USC 371 of PCT/US01/42940, filed Nov. 14, 2001which claims the benefit of U.S. Provisional application No. 60/253,212filed Nov. 27, 2000.

BACKGROUND OF THE INVENTION

Compounds of the formula:

wherein R and R′ are the same or different hydroxy protecting group; areintermediates to pharmaceutically active compounds (see, e.g., U.S. Pat.Nos. 4,075,227, 4,133,814, 4,418,068, 5,552,401 and 5,723,474).

According to the procedures described in the above mentioned patents andother literature references, these intermediates are constructed via anacid catalyzed cyclodehydration reaction of a compound of the formula:

Said cyclodehydration reaction results in an initial mixture of 6- and4-OR isomers (nomenclature refers to the position of the OR group on thebenzothiophene ring) which lie in equilibrium with a pair ofcorresponding aryl migrated isomers. These isomers and theirrelationship to each other are illustrated below where the #(#)nomenclature refers first to the position of the OR group on thebenzothiophene ring and refers second to the position of the phenyl-OR′group on the benzothiophene ring:

The art teaches that the above cyclodehydration can be catalyzed withcertain acids including mineral and organic acids such aspolyphosphoric, phosphoric and methanesulfonic acid, acidic cationexchange resins such as Amberlyst 15, and Lewis acids such as borontrifluoride etherate (see, e.g., Tet. Let., 40:2909, 1999; Org. Proc.Res. & Dev., 3:56, 1999; and U.S. Pat. No.'s 4,358,593, 5,512,684,5,969,157 and 5,977,383). The use of said acids result in varying 6 to4-OR isomer ratios and also vary in their amenability toward isolatingthe 3-aryl isomers, particularly the 6(3) isomer.

For example, when polyphosphoric, phosphoric or methanesulfonic acid isemployed, and R and R′ are both methyl, the 6 to 4-OR isomer ratioranges from about 75:25 to about 80:20. Furthermore, when these acidsare employed, it is difficult to isolate either of the initialcyclization products since the 2-aryl/3-aryl isomer equilibrium isquickly established and favors the 2-aryl isomer.

When Amberlyst 15 is employed, the rearrangement reaction isapproximately fifty to a hundred times slower than the cyclization andhence the 3-aryl isomer can be isolated if desired. However, uponconsumption of the cyclization starting material (about 7 hours when Rand R′ are both methyl and with a 10% weight loading of the Amberlyst 15resin), a significant amount of the 3-aryl isomer (about 7.4%) hasrearranged to the 2-aryl isomer. Similarly, when one of R or R′ ishydrogen and the other is methyl about 8.1% of the 3-aryl isomer in bothcases has rearranged to the 2-aryl isomer. Moreover, use of Amberlyst 15affords about a 88:12 in situ mixture of 6 and 4-OR isomers when R andR′ are methyl, a ratio of 88:12 when R is hydrogen and R′ is methyl and90:10 when R is methyl and R′ is hydrogen.

Although the 3-aryl isomer is accessible when boron trifluoride isemployed, in order to obtain reasonable yields the reaction must be runneat. Furthermore, use of this acid on a compound where R and R′ areboth methyl results in 6 to 4-OR isomer ratios comparable to that ofpolyphosphoric acid (about 6:1). Work-up and product isolation requiresquenching and removing the acid via solvent extractions.

BRIEF SUMMARY OF THE INVENTION

The present invention relates to a process for preparing a compound offormula I:

wherein:

R¹ and R² are independently hydrogen or a hydroxy protecting group;which includes cyclodehydrating a compound of formula II:

in the presence of an acid activated clay or acid activated zeolitecatalyst and in the presence of a suitable solvent.

DETAILED DESCRIPTION OF THE INVENTION

General terms used in the description of chemical formulas bear theirusual meanings. For example, the term “hydroxy protecting group” denotesa group understood by one skilled in the organic chemical arts of thetype described in Chapter 2 of “Protective Groups in Organic Synthesis,2nd Edition, T. H. Greene, et al., John Wiley & Sons, New York, 1991,hereafter “Greene”.

Representative hydroxy protecting groups include, for example, C₁-C₆alkyl and substituted C₁-C₆ alkyl, including methyl, ethyl, isopropyl,cyclopropyl, methoxymethyl, methylthiomethyl, tert-buylthiomethyl,(phenyldimethylsilyl)methoxymethyl, benzyloxymethyl,p-methoxy-benzyloxymethyl, tert-butoxy-methyl; ethoxyethyl,1-(2-chloroethoxy)ethyl, 2,2,2-trichloroethoxymethyl, and2-(trimethylsilyl)ethyl; phenyl and substituted phenyl groups such asp-chlorophenyl, p-methoxyphenyl, and 2,4-dinitrophenyl; benzyl groups;alkylsilyl groups such as trimethyl- triethyl- and triisopropylsilyl;mixed alkylsilyl groups such as dimethylisopropylsilyl, anddiethylisopropylsilyl; acyl protecting groups such as those of thegeneral formula COC₁-C₆ alkyl or COAr; and esters of the general formulaCO₂C₁-C₆ alkyl, or CO₂Ar, where Ar is phenyl or substituted phenyl asdescribed above.

The term “suitable solvent” refers to any solvent, or mixture ofsolvents, inert to the ongoing reaction that sufficiently solubilizesthe reactants to afford a medium within which to effect the desiredreaction. Suitable solvents include methylene chloride, chloroform,1,2-dichloroethane, diethyl ether, acetonitrile, ethyl acetate,1,3-dimethyl-2-imidazolidinone, 1,4-dioxane, tetrahydrofuran, toluene,chlorobenzene, N-methylpyrrolidinone, toluene, xylene, halophenylsolvents such as chlorobenzene, etheral solvents such as glyme, diglymeand ethyleneglycol diether ether, mixtures thereof, and the like.Toluene is a preferred solvent.

The term “acid-activated clay” refers to clays that are derived from thenaturally occurring ore bentonite or the mineral montmorillonite andincludes materials prepared by calcination, washing or leaching withmineral acid, ion exchange or any combination thereof includingmaterials which are often called montmorillonites, acid-activatedmontmorillonites and activated montmorillonites. These clays containboth Bronsted as well as Lewis acid active sites with many of the acidicsites located within the clay lattice. Such clays include, but are notlimited to the materials denoted as, montmorillonite K10,montmorillonite clay, clayzic, clayfen, the Engelhardt series ofcatalysts related to and including X-9107, X9105, Girdler KSF, Tonsiland K-catalysts derived from montmorillonite including but not limitedto K5, K10, K20 and K30, KSF, KSF/O, and KP10. The clays withpredominate Bronsted acidity (KSF, KSF/O and KP10) are preferred withKSF/O and KP10 being more preferred. Another preferred clay is K5. Otherpreferred acid activated clays are X-9105 and X-9107 acid washed claycatalysts marketed by Engelhard.

The term “zeolite” refers to aluminosilicates of the group IA or groupIIA elements and are related to montmorillonite clays that are or havebeen acid activated. They consist of an infinitely extending frameworkof AlO₄ and SiO₄ tetrahedra linked to each other by the sharing ofoxygens. The framework structure contains channels or interconnectingvoids that are occupied by cations and water molecules. Acidic characteris imparted or enhanced by ion exchange of the cations typically withammonium ion and subsequent thermal deamination or calcination. Theacidic sites are primarily located within the lattice pores andchannels. Such zeolites include, but are not limited to, the beta typezeolites as typified by CP814E manufactured by Zeolyst International,the mordenite form of zeolites as typified by CBV21A manufactured byZeolyst International, the Y type zeolites as typified by CBV-720manufactured by Zeolyst International, the ZSM family of zeolites astypified by ZSM-5, and ZSM-11.

The process of the present invention is illustrated in Scheme 1 below.

The instant process involves contacting a compound of formula IIdissolved in a suitable solvent with an acid activated clay or zeoliteto effect a cyclodehydration reaction affording a3-arylbenzo[b]thiophene. As the reaction generates water, conducting thereaction at elevated temperature wherein the water generated can beremoved by distillation is preferred and particularly preferred is theuse of a reaction solvent which forms binary azeotropes with water.Toluene is a preferred solvent for the practice of this invention. Thecyclodehydration reaction rate can be increased by increasing the amountof clay or zeolite catalyst used.

The time required to effect the overall transformation will be dependentupon the temperature at which the reactions are run and the catalystloading. Therefore, the progress of the reactions should be monitoredvia conventional techniques, e.g., HPLC, to determine when the reactionsare substantially complete. Monitoring the progress of chemicalreactions is well within the ordinarily skilled artisan's capability. Ifthe solvent used forms a binary water azeotrope, such as toluene,reaction completion is easily monitored by the azeotropic removal ofwater.

Once reaction completion is achieved the catalyst is removed byfiltration of either the hot reaction mixture or after cooling. Due tothe high yield, the product solution may be used as is in subsequentreactions or the product maybe isolated by conventional methods forsolvent removal.

Some of the catalysts of the present invention may require activationprior to their use. For example, CP814E and CBV21A catalysts arecommercially supplied in the ammonium form where ammonium ions serve asthe cation counterbalancing the negative charge of the aluminum silicatelattice. These catalysts can be activated by heating which drives offammonia converting the cation from an ammonium ion to a proton.Additionally, some catalysts are supplied containing water of hydrationand may require additional activation by thermal or azeotropic drying toremove the water of hydration prior to use.

Preferred compounds of formula II for use in the present process arethose where R¹ is hydrogen, methyl, isopropyl or benzyl, particularlyhydrogen, methyl or benzyl and most particularly, hydrogen or methyl,and those where R² is methyl, isopropyl or benzyl, particularly methyl.Thus, preferred products of the above reaction include, but are notlimited to, 6-hydroxy-3-(4-hydroxy phenyl)benzo[b]thiophene,6-isopropoxy-3-(4-methoxyphenyl)benzo[b]thiophene,6-benzyloxy-3-(4-methoxyphenyl)benzo[b]thiophene and6-methoxy-3-(4-methoxyphenyl)benzo[b]thiophene.

As discussed above, meaningful access to compounds of formula I hasheretofore been limited to use of cation exchange resins such asAmberlyst 15 and Lewis Acid catalysts such as boron trifluoride. The useof the acid catalysts claimed herein provide surprising and unexpectedadvantages relative to Amberlyst 15. For example, upon completeconsumption of the starting material (formula II compound), the presentprocess offers a superior 3 to 2-aryl isomer ratio. In addition, when R¹and R² are both hydroxy protecting groups, the present process offers asuperior 6 to 4-OR¹ isomer product ratio.

With a 10% weight loading of the Amberlyst 15 resin, completeconsumption of a compound of formula II, where both R¹ and R² aremethyl, is observed at 7 hours. At this time, the reaction mixtureconsists of 82.6% 6(3) isomer and 6.6% 6(2) isomer. Thus, 7.4% of the6(3) isomer present has already undergone migration to the 6(2) isomer.In contrast, with the clay catalyst X-9107, loaded wet at 15%,consumption of the above starting material is observed in 3 hours. Atthis point, the reaction mixture consists of 95.8% 6(3) isomer and 3.9%6(2) isomer. Thus, the extent of aryl migration using an acid of thepresent invention is only 3.9%.

The following table compares the 6 to 4-OR¹ isomer ratio observed incyclodehydrations of a compound of formula II, where both R¹ and R² aremethyl, employing Amberlyst 15, polyphosphoric acid, boron trifluorideetherate, and representative acid catalysts of the present invention.

TABLE 1 6- 4- Acid Catalyst Isomer Isomer Polyphosphoric Acid 78% 22%Amberlyst A15 Resin 89% 11% Boron Trifluoride 86% 14% Bentonite Clay(X-9107) 98% 2% Montmorillonite KP10 96% 4% Montmorillonite KSF 96% 4%Montmorillonite KSF/O 95% 5% Montmorillonite K5 98% 2% Montmorillonite92% 8% (Aluminum pillared clay) Montmorillonite K20 93% 7%Montmorillonite K10 92% 8% Montmorillonite K30 93% 7% Zeolyst CBV-72096% 4%

For a compound of formula II where both R¹ and R² are methyl, theaverage in situ 6 to 4-OR¹ isomer ratio in twelve replicate lab trialsusing Amberlyst 15 was 88% to 12% while the average isolated yield ofthe 3-aryl isomer was 78.6% (see Example 8). Correspondingly in 3identical scale trials using the Bentonite X-9107 catalyst the averagein situ 6- to 4-OR¹ isomer ratio was 98% to 2% and the average isolatedyield of the 3-aryl isomer was 89.7% (see Example 7).

The use of the acid catalysts claimed herein also provide advantagesrelative to the boron trifluoride promoted reaction. Unlike the borontrifluoride promoted process, the solvent used in the present processcan be recycled. Furthermore, unlike the boron trifluoride promotedprocess, workup and isolation of the product prepared by the presentprocess simply requires filtration to remove the insoluble acidcatalyst. The desired product can then be further used in solution orisolated by simple solvent removal. Moreover, when R¹ and R² are bothhydroxy protecting groups, the present process offers a superior 6 to4-OR¹ isomer product ratio.

To assess potential effects of catalyst loading on the cyclodehydrationreaction rate, and on the 6- to 4-OR¹ isomer ratio, reactions of acompound of formula II where R¹ is H and R² is methyl and a compound offormula II where R¹ and R² are both methyl, at two differentconcentrations in toluene (146 mM and 729 mM), were run with a 5%, 15%and 25% weight loading of Bentonite Clay X-9107 relative to the weightof substrate charged. The resulting 6 to 4-OR¹ isomer ratio in thecyclodehydration with both of the above formula II compounds remainedconstant regardless of the clay catalyst loading. The resulting 6 to4-OR¹ isomer ratio was also independent of reaction concentration.Catalyst loading, as well as the reaction concentration, can impact thereaction rate with higher reaction concentrations and, in particular,higher catalyst loading resulting in faster reaction rates.

In another embodiment of the present invention, a compound of formula I,either after isolation or after preparation in situ, may be treated withpolyphosphoric acid, or mixture of polyphosphoric and phosphoric acids,or treated with methanesulfonic acid to effect aryl migration andconversion to a compound of formula III as described in U.S. Pat. Nos.4,380,635, 5,969,157 and 5,512,684, the teachings of which are herebyincorporated by reference. The improvement in 6 to 4-OR¹ isomer ratiodiscussed above, using the acids of the present invention for thecyclodehydration reaction, is reflected in isolated yields of theformula III compound.

In another preferred embodiment, a compound of formula III is acylated,optionally deprotected and optionally salified to form a compound offormula IV:

or a pharmaceutical salt thereof; wherein:

p is 0, 1 or 2; and

R³ and R⁴ are independently C₁-C₄ alkyl, or combine together with thenitrogen to which they are attached to form a piperidinyl, pyrrolidinyl,methylpyrrolidinyl, dimethylpyrrolidinyl, morpholino, dimethylamino,diethylamino, or 1-hexamethyleneimino ring.

The acylation and optional deprotection and salification reactions maybe performed essentially as described in U.S. Pat. No.'s 4,380,635,4,418,068, 5,512,684, 5,523,416, 5,629,425, 5,731,327, 5,969,157 and5,977,383 the teachings of each are herein incorporated by reference.The hydrochloride salt of a compound of formula IV where R¹ and R² ishydrogen and R³ and R⁴ combine to form a piperidinyl ring is a preferredproduct.

In another preferred embodiment, a compound of formula III may be3-halogenated, S-oxidized, have the 3-halo group displaced, reduced,optionally deprotected, and optionally salified to prepare a compound offormula V:

p is 0, 1 or 2;

R³ and R⁴ are independently C₁-C₄ alkyl, or combine together with thenitrogen to which they are attached to form a piperidinyl, pyrrolidinyl,methylpyrrolidinyl, dimethylpyrrolidinyl, morpholino, dimethylamino,diethylamino, or 1-hexamethyleneimino ring; and

X is O or CO; or pharmaceutical salt thereof.

In a particularly preferred embodiment, a compound of formula I may beused to prepare a compound of formula VI and VII:

The 3-halogenation, oxidation, nucleophilic displacement of halo,reduction, and optional deprotection and salification reactions may beperformed essentially as described in U.S. Pat. No.'s 5,510,357,5,512,684, 5,523,416, 5,723,474, 5,969,157 and 5,977,383 and PCTPublication No.'s WO 01/09115 and WO 01/09116, the teachings of whichare hereby incorporated by reference. The hydrochloride salt of compoundof formula V where R¹ is hydrogen, R² is methyl, and R³ and R⁴ combineto form piperidinyl is preferred.

The acid activated clays and zeolites of the present invention aretypically commercially available, however, general methods for theirpreparation are described in Trans. Soc. Min. Eng., 282:1901-10, 1987and references therein. Compounds of formula II are known in the art andare generally commercially available or can be prepared by methods wellknown in the art from readily available starting materials. Thecompounds of formula II may be prepared according to proceduresdescribed in U.S. Ser. No. PCT/US01/42939 filed on the same day as Ser.No. 10/415,569.

Preparations Preparation 1 Representative Procedure for CatalystActivation

A 3.0 gm sample of zeolite catalyst CBV-21A was heated for approximately4 hours at 350° C. prior to cooling and immediate use. A similar amountof zeolite catalyst CP814E was activated in a similar manner.

EXAMPLES Example 1 6-Methoxy-3-(4-methoxyphenyl)benzo[b]thiophene

Toluene (100 ml), α-(3-methoxyphenylthio)-4-methoxyacetophenone (4.21gm) and “acid-activated clay” (Engelhard X-9107 0.63 gm) were combinedand heated to reflux. The water present in the catalyst as well as thewater generated in the reaction was removed using a Dean Stark trap. Thedisappearance of starting material as well as the appearance of productwas monitored by HPLC. After 2 hour at reflux less than 1% of thestarting material remained. By HPLC the reaction mixture consisted of96.7% 6-methoxy-3-(4-methoxyphenyl)benzo[b]thiophene, 1.1%6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene, 2.1%4-methoxy-3-(4-methoxyphenyl)benzo[b]thiophene and 0.1%4-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene. HPLC system used tomonitor the reaction:

-   -   Column: Zorbax SB C18 4.6×150 mm, 3.5 micron    -   Buffer: 25 nM Phosphate Buffer, pH 2.5 (2.38 gm    -   KH₂PO₄ pH to 2.5 with H₃PO₄ (85%/L Millipore water)    -   Organic: Acetonitrile    -   Column Temperature: 40° C.    -   Flow rate: 1.5 ml/min    -   Detection: UV, 280 nm    -   Injection Volume: 10 ml    -   Run time: 37 minutes    -   Gradient: Time in minutes (% ACN) 0(48); 3.3(48);    -   28.6(55); 32(55); 32.6(48); 37(48).

Example 2 6-Hydroxy-3-(4-methoxyphenyl)benzo[b]thiophene

Toluene (100 ml), α-(3-hydroxyphenylthio)-4-methoxyacetophenone (4.00gm) and “acid-activated clay” (Engelhard X-9107 0.6 gm) were combinedand heated to reflux. The water present in the catalyst as well as thewater generated in the reaction was removed using a Dean Stark trap. Thedisappearance of starting material as well as the appearance of productwas monitored by HPLC. After 6 hour at reflux less than 0.3% of thestarting material remained. By HPLC the reaction mixture consisted of86.2% 6-hydroxy-3-(4-methoxyphenyl)benzo[b]thiophene, 5.1%6-hydroxy-2-(4-methoxyphenyl)benzo[b]thiophene, 8.5%4-hydroxy-3-(4-methoxyphenyl)benzo[b]thiophene and 0.2%4-hydroxy-2-(4-methoxyphenyl)benzo[b]thiophene. HPLC system used tomonitor the reaction same as in Example 1 except gradient as follows:0(38); 3.3(38); 28.6(45); 32(45); 32.6(38); 37(38).

Example 3 6-Methoxy-3-(4-hydroxyphenyl)benzo[b]thiophene

Toluene (100 ml), α-(3-methoxyphenylthio)-4-hydroxyacetophenone (4.00gm) and “acid-activated clay” (Engelhard X-9107 0.6 gm) were combinedand heated to reflux. The water present in the catalyst as well as thewater generated in the reaction was removed using a Dean Stark trap. Thedisappearance of starting material as well as the appearance of productwas monitored by HPLC. After 7 hour at reflux less than 1% of thestarting material remained. By HPLC the reaction mixture consisted of91.7% 6-methoxy-3-(4-hydroxyphenyl)benzo[b]thiophene, 2.2%6-methoxy-2-(4-hydroxyphenyl)benzo[b]thiophene, 5.8%4-methoxy-3-(4-hydroxyphenyl)benzo[b]thiophene and 0.3%4-methoxy-2-(4-hydroxyphenyl)benzo[b]thiophene. HPLC system used tomonitor the reaction same as Example 2.

Example 4 6-Hydroxy-3-(4-hydroxyphenyl)benzo[b]thiophene

Toluene (100 ml), α-(3-hydroxyphenylthio)-4-hydroxyacetophenone (3.80gm) and “acid-activated clay” (Engelhard X-9107 0.57 gm) were combinedand heated to reflux. The water present in the catalyst as well as thewater generated in the reaction was removed using a Dean Stark trap. Thedisappearance of starting material as well as the appearance of productwas monitored by HPLC. After 7 hour at reflux less than 12% of thestarting material remained. By HPLC the ratio of 6 to 4-OR¹benzo[b]thiophene isomers was 84.1% to 15.8%. HPLC system used tomonitor the reaction same as Example 1 except gradient as follows:0(28); 3.3(28); 28.6(35); 32(35); 32.6(28); 37(28).

Example 5 Catalyst Screening for Cyclodehydration ofα-(3-methoxyphenylthio)-4-methoxyacetophenone

Toluene (100 ml), α-(3-methoxyphenylthio)-4-methoxyacetophenone (4.21gm) and 0.63 gm of catalyst were combined and heated to reflux. Thewater present in the catalyst as well as the water generated in thereaction was removed using a Dean Stark trap. The disappearance ofstarting material as well as the appearance of product was monitored byHPLC using the HPLC system provided in Example 1.

Example 6 Catalyst Screening for Cyclodehydration ofα-(3-hydroxyphenylthio)-4-methoxyacetophenone

Toluene (100 ml), α-(3-hydroxyphenylthio)-4-methoxyacetophenone (4.00gm) and 0.6 gm of catalyst were combined and heated to reflux. The waterpresent in the catalyst as well as the water generated in the reactionwas removed using a Dean Stark trap. The disappearance of startingmaterial as well as the appearance of product was monitored by HPLCusing the HPLC system provided in Example 2. The results of thisscreening are indicated below in Table 2.

TABLE 2 Reaction Total Total time Catalyst 6-isomer 4-isomer (hours)Engelhard (X-9107) 92%  8% 5 Montmorillonite K5 89% 11% >8Montmorillonite K10 82% 18% >8 Montmorillonite K20 84% 16% >8Montmorillonite K30 82% 18% >8 Montmorillonite KSF 86% 14% >8Montmorillonite 90% 10% 2 KSF/O Montmorillonite 90% 10% 7 KP10Montmorillonite 86% 14% >8 (Aluminum pillared clay) Zeolyst CP814E 85%15% >8 Zeolyst CBV-21A 83% 17% >8 Zeolyst CBV-720 75% 25% 2

Example 7 6-Methoxy-2-(4-methoxyphenyl)benzo[b]thiophene

Toluene (300 ml), α-(3-methoxyphenylthio)-4-methoxyacetophenone (97.5gm) and “acid-activated clay” (Engelhard X-9107 14.6 gm) were combinedand heated to reflux. The water present in the catalyst as well as thewater generated in the reaction was removed by using a Dean Stark trap.Heating was continued until water removal ceased. At this point thereaction mixture was held at reflux for an additional 1 hour. After atotal of 4 hours the ratio of total 6- to 4-OR¹ isomers was determinedusing the HPLC system given in Example 1. The catalyst was removed byhot filtration and washed with 30 ml of hot toluene. To the combinedfiltrate and wash was added 34.5 gm of methanesulfonic acid. Theresulting reaction mixture was stirred for approximately 5 hours at85-90° C. At 85-90° C. 135 ml of heptanes was added and the resultingmixture stirred for 1 hour at 85-90° C. The reaction mixture wasadjusted to 75-85° C., stirred for 3 hours and 240 ml of isopropanolslowly added followed by stirring at 80-90° C. for 30 minutes. Theresulting slurry was cooled to 0-10° C., stirred for 2 hours, a mixtureof 63 ml of toluene and 27 ml of isopropanol added, the solids isolatedby filtration, washed with 78 ml of 4:1 toluene/isopropanol and vacuumdried at 40° C. to afford6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene. The results of threereplicate trials are shown below in Table 3.

TABLE 3 in situ in situ % 6-OR¹ % 4-OR¹ Isolated Trial # isomer isomerYield Purity 1 98.0% 2.0% 88.1% 99.4% 2 97.0% 3.0% 91.0% 99.0% 3 97.5%2.5% 89.9% 99.4% Average 97.5% 2.5% 89.7% 99.3%

Example 8 6-Methoxy-2-(4-methoxyphenyl)benzo[b]thiophene

Toluene (600 ml), α-(3-methoxyphenylthio)-4-methoxyacetophenone (195 gm)and 19.5 gm of Amberlyst 15 resin were combined and heated to reflux.The water present in the resin as well as the water generated in thereaction was removed by using a Dean Stark trap. Heating was continueduntil water removal ceased. At this point the ratio of total 6- to 4-OR¹isomers was determined using the HPLC system given in Example 1. Theresin was removed by hot filtration and washed with 60 ml of hottoluene. To the combined filtrate and wash was added 69 gm ofmethanesulfonic acid. The resulting reaction mixture was stirred forapproximately 5 hours at 85-90° C. At 85-90° C. 270 ml of heptanes wasadded and the resulting mixture stirred for 1 hour at 85-90° C. Thereaction mixture was adjusted to 75-85° C., stirred for 3 hours and 480ml of isopropanol slowly added followed by stirring at 80-90° C. for 30minutes. The resulting slurry was cooled to 0-10° C. and stirred for 2hours. A mixture of 126 ml of toluene and 54 ml of isopropanol added,the solids isolated by filtration, washed with 156 ml of 4:1toluene/isopropanol and vacuum dried at 40° C. to afford6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene. The results of twelvereplicate trials are shown below in Table 4.

TABLE 4 in situ in situ % 6-OR¹ % 4-OR¹ Isolated Trial # isomer isomerYield Purity  1 88.0% 12.0% 76.6% 98.8%  2 87.5% 12.5% 78.3% 97.2%  388.0% 12.0% 78.8% 99.0%  4 87.0% 13.0% 77.5% 98.4%  5 89.0% 11.0% 79.8%99.1%  6 88.5% 11.5% 78.4% 100.8%  7 88.5% 11.5% 79.0% 101.4%  8 87.0%13.0% 78.8% 100.3%  9 87.5% 12.5% 79.3% 100.5% 10 88.0% 12.0% 77.5%102.9% 11 88.0% 12.0% 78.8% 100.1% 12 87.0% 13.0% 80.3% 100.6% Average87.8% 12.2% 78.6% 99.9%

1. A process for preparing a compound of formula I:

wherein: R¹ and R² are independently hydrogen or a hydroxy protectinggroup; which comprises cyclodehydrating a compound of formula II:

in the presence of an acid activated clay or acid activated zeolitecatalyst and in the presence of a suitable solvent.
 2. The process ofclaim 1 wherein the compound of formula II is a compound where R¹ is H,benzyl, methyl or isopropyl and the compound of formula III is acompound where R² is H, benzyl, methyl or isopropyl.
 3. The process ofclaim 2 wherein the compound of formula II is a compound where R¹ ismethyl or benzyl and wherein the compound of formula III is a compoundwhere R² is methyl.
 4. The process according to claim 3 wherein thesolvent is toluene, the catalyst is Bentonite X-9107 and the process isperformed at the reflux temperature of the mixture.
 5. The processaccording to claim 3 wherein the solvent is toluene, the catalyst is K5and the process is performed at the reflux temperature of the mixture.6. In a process for preparing a compound of formula V:

or an acid addition salt thereof; wherein: p is 0, 1 or 2; R³ and R⁴ areindependently C₁-C⁴ alkyl, or combine together with the nitrogen towhich they are attached to form a piperidinyl, pyrrolidinyl,methylpyrrolidinyl, dimethylpyrrolidinyl, morpholino, dimethylainino,diethylamino, or 1-hexamethyleneimino ring; and X is O or CO; theimprovement which comprises the process of claim
 1. 7. The process ofclaim 6 wherein the compound of formula V is of the formula VI:

or a pharmaceutically acceptable salt thereof.
 8. The process of claim 6wherein the compound of formula V is of the formula VII:

or a pharmaceutically acceptable salt thereof.